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Oncogene-induced senescence underlies the mutual exclusive nature of oncogenic KRAS and BRAF

Oncogene volume 35, pages 1328–1333 (2016)Cite this article

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Abstract

KRAS and BRAF are among the most commonly mutated oncogenes in human cancer that contribute to tumorigenesis in both distinct and overlapping tissues. However, KRAS and BRAF mutations are mutually exclusive; they never occur in the same tumor cell. The reason for the mutual exclusivity is unknown, but there are several possibilities. The two mutations could be functionally redundant and not create a selective advantage to tumor cells. Alternatively, they could be deleterious for the tumor cell and induce apoptosis or senescence. To distinguish between these possibilities, we activated the expression of BRAFV600E and KRASG12D from their endogenous promoters in mouse lungs. Although the tumor-forming ability of BRAFV600E was higher than KRASG12D, KRASG12D tumors were larger and more advanced. Coactivation of BRAFV600E and KRASG12D markedly reduced lung tumor numbers and overall tumor burden compared with activation of BRAFV600E alone. Moreover, several tumors expressed only one oncogene, suggesting negative selection against expression of both. Similarly, expression of both oncogenes in mouse embryonic fibroblasts essentially stopped proliferation. The expression of both oncogenes hyperactivated the MEK-ERK-cyclin D pathway but reduced proliferation by increasing the production of p15, p16 and p19 proteins encoded by the Ink4/Arf locus and thereby increased senescence-associated β-galactosidase-positive cells. The data suggest that coexpression of BRAFV600E and KRASG12D in early tumorigenesis leads to negative selection due to oncogene-induced senescence.

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Acknowledgements

We thank R Ister for technical assistance. This study was supported by grants from the Swedish Cancer Society, the Swedish Research Council, the Göran Gustafsson Foundation, the Swedish Children’s Cancer Fund, BioCARE—a strategic research program at the University of Gothenburg, and Ingabritt and Arne Lundberg’s Research Foundation (to MOB); and the Assar Gabrielsson Foundation (to VIS).

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Authors and Affiliations

  1. Department of Molecular and Clinical Medicine, Sahlgrenska Cancer Center, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden

    J Cisowski, V I Sayin, C Karlsson & M O Bergo

  2. Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden

    V I Sayin

  3. Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden

    M Liu

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  1. J Cisowski
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  2. V I Sayin
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  3. M Liu
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  4. C Karlsson
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  5. M O Bergo
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Correspondence to M O Bergo.

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The authors declare no conflict of interest.

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Cisowski, J., Sayin, V., Liu, M. et al. Oncogene-induced senescence underlies the mutual exclusive nature of oncogenic KRAS and BRAF. Oncogene 35, 1328–1333 (2016). https://doi.org/10.1038/onc.2015.186

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  • DOI: https://doi.org/10.1038/onc.2015.186

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